ROCKVILLE, Maryland—The death of a patient in an inflammatory arthritis gene therapy trial prompted the US FDA to stop the study and has led some rheumatologists to wonder whether gene therapy has any future in arthritis and related diseases.

The phase I/II trial conducted by Targeted Genetics Corp of tgAAC94 for treatment of active inflammatory arthritis is on hold until the FDA ascertains the cause of the patient's death. The participants already enrolled in the study will continue to be followed and monitored.

"Whenever there is an unexplained death in any trial, particularly small trials, let alone the sorcery around gene therapy, there is huge angst," explained Lee S. Simon, MD, rheumatologist at Harvard Medical School, in Boston, Massachusetts. "What actually may have happened here is weird and does need to be explained, and until things are really totally transparent, it will be difficult to get patients in rheumatic diseases to voluntarily sign up for gene therapy trials."

Arthritis Foundation President and CEO John H. Klippel, MD, said in a statement, "It is important to carefully review the safety, risks and benefits of any new investigational arthritis treatment, and we applaud the FDA for their prompt action in informing the public of this occurrence and suspending the clinical trial while more is learned about the cause of this death. Gene therapy may hold great promise as a therapy for people with arthritis, but is still very much in the early phases of investigation."

Placebo-controlled trial of anti-TNF gene therapy

The trial included 127 patients with active inflammatory arthritis who were being treated with injections of the antitumor necrosis factor-α (TNF-α ) receptor gene therapy or placebo. The  gene transfer vector was a recombinant adeno-associated virus (AAV), which was injected directly into affected knee, ankles, wrist, metacarpophalangeal or elbow joints. AAV is a naturally occurring virus that has not been associated with any disease in humans, according to the company.

Targeted Genetics has been developing tgAAC94 as a potential additional treatment for patients with one or more joints that do not fully respond to systemic TNF inhibitor therapy. The experimental product uses a recombinant AAV (rAAV) vector to deliver a DNA sequence that encodes a soluble form of the TNF-α  receptor (TNFR: Fc). Direct injection of tgAAC94 into affected joints leads to localized production of TNFR:Fc within the joint and could potentially "wipe up" bothersome caches of TNF-mediated inflammation that persist despite systemic TNF inhibition.

The patient who died had a serious adverse reaction after the second injection, although whether the death was treatment-related is not yet known. Overall, 74 of the trial's 127 subjects have received second doses of the active treatment, according to the company. More than 100 patients enrolled in the trial have been treated without known serious events, the FDA said.

"Targeted Genetics is cooperating with FDA's investigation and has agreed to provide the agency with ongoing results from various tests and all other information it is compiling that may help determine the cause of this patient's death," according to an FDA statement.
The FDA stated that it was not aware of similar adverse events occurring in other gene therapy trials either with tgAAC94 or other genes in AAV vectors, but as a precaution the agency is reviewing all ongoing trials involving any use of AAV. AAV is widely used in gene therapy trials in many diseases and has been used in cystic fibrosis gene therapy trials for several years.

"The clinical course that this individual experienced has, to our knowledge, never been seen as a consequence of exposure to AAV vectors or naturally occurring AAV," said H. Stewart Parker, president and CEO of Targeted Genetics in a press release. "We continue to work closely and diligently with the FDA and the study's independent Data Safety Monitoring Board to determine the cause of the serious adverse event as quickly as possible."

Interim data pointed toward safety

The study initiated in October 2005 aimed to assess the safety and potential efficacy of different doses of tgAAC94. In March 2006, Targeted Genetics received FDA approval to include a higher dose group and increase the number of patients.

The interim data supported the safety and tolerability of single and repeat intraarticular injections of tgAAC94 to affected joints at doses up to 1x10¹³ DNase Resistant Particles per milliliter (DRP/mL) of joint fluid in subjects with and without systemic TNF-α antagonists. This data also suggested that treatment with tgAAC94 may lead to improvements in signs and symptoms of arthritis in injected joints.